Transplantation of pancreatic islets into patients and animal models with TID (Type 1 Diabetes or Insulin-Dependant Diabetes), improves glycemic control leading to amelioration of markers for diabetic complications. Yet, the current protocols for transplantation and maintenance of 'Insulin-free' status require a lifetime of toxic immunosuppression. The focus of this center grant is the determination of protocols to inhibit autoimmunity through tolerance induction, but the generation of tissue grafts to which the immune system is ignorant or ineffective would serve this end as well. Islets from the ALR mouse strain maintain an unusual genetic resistance to functional impairment and killing by autoimmune effectors and genetic mapping has isolated the genomic locations of the ALR-derived protection. Our goal is to determine if the heritable resistance of ALR islets to autoimmunity will extend to a defense of both allo-graft and auto-graft rejection. To enable this progress a dense polymorphism map will be generated across the ALR derived T1D-resistance loci. This map will facilitate the generation of congenic strains for use in transplantation experiments. Testing of the congenics will proceed in two separate systems. The ALR-derived loci will be tested for the potential to resist destruction when transplanted into diabetic and allogeneic C57BL/6 hosts. ALR and congenic islets will also be tested in NOD transplantation systems where both allo-recognition and autoimmunity will present immune stress. If the results mirror the preliminary transplantation work with ALR, where these islets exhibited resistance to allo and autoimmune destruction, then the importance of the results are clear. Therefore, our work could possibly translate to human clinical practice leading to reductions in the number of islets need to create insulin independence and decreases in or possible complete removal of immunosuppressive agents from patients with islet grafts.